Depression, genetics, and why SSRIs may not be your thing

I’m currently consuming neuroscience papers like crazy as part of the
talk I’m giving at OSCON tomorrow. I’m currently reading an
excellent overview on serotonin transporters¹, and in particular looking at
knock-out mice that can’t synthesize the serotonin transporter—the molecule
which gets serotonin out of the synaptic cleft and back into neurons.

Mice lacking the transporter show a huge number of altered behaviours in line
with depression and other mental illnesses in humans. They tend to have lots of
serotonin sloshing around in their synaptic clefts (because it can’t get back
into their neurons), and neurons which fire based upon serotonin signals appear
to be less responsive (there’s much less clear “on-off” signalling).

Almost all our drugs for treating depression involve increasing the amount of
serotonin and/or other monoamines (such as noradrenaline) in the synaptic
cleft. But if you’re a knock-out mouse, you already have oodles of this stuff
floating around there. We’re not sure if antidepressants alleviate the signs of
depression in these mice, because giving them antidepressants
increases serotonin to levels that are neurotoxic.

Short promoter regions, greater aversion to SSRIs¹

Humans show a polymorphism in the promoter region of the serotonin transporter
gene. Those with short promoter regions appear to have less transporters
produced, and they also show a significant aversion to continuing traditional
anti-depressants. The theory is that treatment causes mild
serotonin syndrome.

The more I research, the more it becomes immensely apparent that depression is
not a disease, it’s not something with a single cause. It’s a syndrome.
There’s a number of underlying pathologies, any of which can result in the
state we know as “depression”. It’s no wonder that only about half of patients
respond fully to treatment² (therapy AND drugs).

Your genetics can make a big difference to depression susceptibility⁴

We know genetics explains about 50% of susceptibility to depression³, but
there’s still this big 50% that isn’t explained. There’s a lot of evidence
that’s pointing towards stress, and we think there might be something to do
with Brain-Derived Neurotrophic Factor, but as a syndrome the
involvement of stress and/or BDNF may be implicated in some cases of
depression, but not others.

One thing that is certain is that depression absolutely sucks, and the more
we’re able to understand the underlying causes and possible treatments, the
better.

Edit: The next day I did indeed give a presentation on the neuroscience
behind depression, along with my personal experiences. You can
watch it online.